7. Project Summary/Abstract PTI-125 is a novel compound with a novel target, designed to treat and slow the progression of Alzheimer's disease (AD). PTI-125 binds with femtomolar affinity to a particular site on filamin A (FLNA), a scaffolding protein we recently demonstrated is critical to beta amyloid's toxicity. Beta amyloid1-42 (A?42) exerts its toxic effects by hijacking the ?7-nicotinic acetylcholine receptor (?7nAChR) and signaling via this receptor to hyperphosphorylate tau. In addition to disrupting normal function of ?7nAChR and tau, this toxic signaling leads to the signature tangles and plaques found in brains of AD patients. We have shown that this toxic signaling of A?42 requires FLNA recruitment to ?7nAChR. The recruited FLNA stabilizes A?42-?7nAChR complexes (promoting a femtomolar interaction) to enable further A?42 piling and the toxic signaling that leads to eventual neurodegeneration. PTI-125 binding to FLNA prevents or reverses the FLNA ? ?7nAChR association and A?42's tight binding and subsequent toxic effects. A?42 also impairs the function of two other receptors that are pivotal to neuronal survival, cognition and memory, the NMDA receptor and the insulin receptor. By binding to FLNA, PTI-125 restores normal function of all three receptors. PTI-125 also disrupts a similar association of FLNA with toll-like receptor-4 (TLR-4), a receptor responsible for releasing inflammatory cytokines. Hence, PTI-125 has a second function of blocking the inflammation noted in AD brain. Preclinical efficacy was demonstrated in an acute ICV A?42 infusion mouse model, in normal aged mice, and most importantly, in human postmortem AD brain tissue. The effective concentration in postmortem human brain is as low as 1 pM. PTI-125 has completed and cleared all IND-enabling studies, and the GMP manufacture and Phase I clinical drug supply is underway. The 28-day toxicity studies demonstrated a 50-fold safety margin between the NOAEL (no observable adverse event level) in rat and a 15-fold safety margin in dog compared to the efficacious doses in both mouse efficacy studies. PTI-125 is rapidly absorbed and eliminated with nearly 100% oral bioavailability, dose proportional PK and no accumulation. Metabolic profiling showed minimal metabolism across species. In Phase I of this Fast-track proposal, we will file an IND. With a successful IND submission, we will initiate Phase II: a single ascending dose (SAD) study in healthy volunteers, followed by 3-month toxicity studies in two species. Further work outside this proposal included a SAD clinical study in AD patients, which will determine the dosing frequency for a multi-dose PK and safety study in AD patients. The 3-month toxicity studies will support clinical trials of 3-month duration but are also needed to determine doses for the chronic toxicity studies needed to support clinical trials of any duration as well as an NDA.